Future of Radiotherapy in Nasopharyngeal Carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) is a malignancy with unique clinical biological profiles such as associated Epstein-Barr virus infection and high radiosensitivity. Radiotherapy has long been recognized as the mainstay for the treatment of NPC. However, the further efficacy brought by radical radiotherapy has reached the bottleneck in advanced patients, who are prone to develop recurrence and distant metastasis after treatment. The application of photon therapy makes it possible for radiation dose escalation in refractory cases and may provide second chance for recurrent patients with less unrecoverable tissue damage. The concept of adaptive radiotherapy is put forward in consideration of target volume shrinkage during treatment. The replanning procedure offers better protection for the organ at risk. However, the best timing and candidates for adaptive radiotherapy is still under debate. The current tendency of artificial intelligence in NPC mainly focuses on image recognition, auto-segmentation and dose prediction. Although artificial intelligence is still in developmental stage, the future of it is promising.

To further improve the efficacy of NPC, multimodality treatment is encouraged. In-depth studies on genetic and epigenetic variations help to explain the great heterogeneity among patients, and could further be applied to precise screening and prediction, personalized radiotherapy and the evolution of targeted drugs. Given the clinical benefit of immunotherapy in other cancers, the application of immunotherapy, especially immune checkpoint inhibitor, in NPC is also of great potential. Results from ongoing clinical trials combining immunotherapy with radiotherapy in NPC are expected.

Introduction

Nasopharyngeal carcinoma (NPC), originated from the lining of the nasopharynx, is a malignancy caused by multiple factors involving genetic variants, environmental factors, and Epstein-Barr virus (EBV) infection.¹ Due to its radiosensitive behavior and deep-seated anatomic location, radiotherapy (RT) has been established as the primary treatment method since 1965. Before the 1990s, conventional two-dimensional radiotherapy (2DCRT) is the main radiotherapeutic technology. However, conventional RT to the head and neck is associated with severe acute and late toxicities for its limitation in conformity degree. Mucositis is the most common acute side-effect caused by radiation to the oral mucosa, accompanied by severe pain, swallowing difficulty and malnutrition. Other acute and late effects included xerostomia and dysgeusia, hearing loss, consistent xerostomia, mandibular osteoradionecrosis and dysphagia.^2–4 Even if there is no obvious influence on the survival outcomes, the quality of life is severely impaired.

In the last decade, intensity modulated radiotherapy (IMRT) has replaced 2DCRT, which is a major step forward in the treatment of NPC.⁵ Through the use of a dynamic multileaf collimator, IMRT can modulate both the shape and intensity of individual beams to achieve an optimal dose distribution to tumor area. A more conformal dose distribution enables IMRT to minimize the dose delivery to organ at risk (OAR), including the brain stem, spinal cord, and optic chiasm.^6–8 The application of daily image guidance (image-guided radiotherapy) also gives rise to a decreased dose in the planning target volume (PTV), which further decreases normal tissue exposure.⁹ In terms of late toxicity, the incidence and severity of radiation-induced trismus and delayed xerostomia are also reduced by IMRT.^8,10 Moreover, IMRT greatly enhances conformity with the target dose and facilitates dose escalation,⁷ which further improves the survival outcome of NPC patients according to previous studies.^11–13

Even though IMRT allows increased conformality relative to 2DCRT, late toxicities including consistent xerostomia and dysphagia remain a key issue.¹⁴ Therefore, a new radiotherapy method to further decrease dose to normal tissues is warranted.

The application of photon therapy

Unlike photon radiation, proton therapy has the advantage of sharp dose fall off at the edge of the tumor, thus the dose delivered to adjacent normal tissues decreases remarkably. This strength makes it possible to protect OARs and provide opportunities for potential dose escalation in tumor area.

The application of proton radiotherapy (PRT) was first encouraged by successe in the treatment of chordomas and chondrosarcomas of the skull base¹⁵ and intraocular melanoma. Recently, there is of increasing interest in the use of PRT for treating cancers of the head and neck including NPC.¹⁶ Applied in the treatment of NPC, proton therapy could achieve following objectives: (I) dose escalation for local advanced patients, whose local tumor control is currently limited by an inability to sufficiently deliver therapeutic doses. (II) Minimizing exposures to normal tissues and further decreasing toxicity.

Compared with IMRT, several studies demonstrated that intensity modulated proton therapy (IMPT) could better spare normal tissues while maintaining effective delivery of the dose to the target in treatment of NPC.^17–21 Cozzi L et al compared three-dimensional conformal radiation with IMRT and proton therapy, verified that patients treated with proton therapy had the best dose coverage with respect to PTV area. Meanwhile, a better protection of spinal cord and parotid gland was achieved.²⁰ Another study launched by Taheri-Kadkhoda found that IMPT plans for NPC were associated with lower doses exposure to the larynx/esophagus, oral cavity, and parotid glands, which area is of greatest potential impact on acute and chronic toxicities affecting patients’ quality of life, compared with IMRT plans.^17,22

In terms of treatment effect, several studies reported the evidence of clinical benefit from proton RT with relatively small sample. Researchers from Massachusetts General Hospital presented their experience in proton therapy for local advanced NPC patients.²³ 19 patients with T4 stage were involved in this study. In their cohort, the 3 year overall survival, progression-free survival and locoregional relapse free survival 74%, 75 and 92%. Data from MD Anderson Cancer Center showed that after a median follow-up of 2 years, no patients out of nine developed local or regional recurrence. A Phase II study launched by MGH evaluated the treatment effect of the combination of proton–photon therapy (70 Gy in 35 daily fractions) and concurrent chemotherapy (cisplatin and fluorouracil) (NCT00592501). With the median follow up time of 28 months, the local control rate was 100%, while the 2 year overall survival and disease-free survival (DFS) were 100 and 90%. Gastrostomy tube placement was the main toxic effect (48%). Other toxic effects included hearing loss (29%), weight loss (38%). Inspiringly, no grade ≥3 xerostomia case was reported.²⁴

Promising data as we may see, the effectiveness of proton therapy needs to be further studied. Firstly, the dosimetric superiority of proton radiotherapy was achieved by the use of pencil-beam scanning and IMPT, which requires further development, including in vivo verification previous to clinical implementation. Secondly, worldwide cancer centers for delivering proton therapy are still limited, as long as the clinical trials with large sample size to study the best candidate for proton therapy. Therefore, studies with comparative results between proton therapy and IMRT are expected.²⁵ The superiority of IMPT in dose distribution, toxicity and efficacy was summarized in Table 1.

Table 1. .

The superiority of IMPT in dose distribution, toxicity and efficacy

Parameter	Superiority of IMPT	Reference
Dose distribution	I. More accurate dose coverage with respect to tumor area II. Lower doses exposure to the normal tissues III. Effective delivery of the dose to the target	17–21
Toxicity	I.Better protection of OAR II. Fewer acute and chronic toxicities	17,20,22
Efficacy	I.Satisfactory local control rate II. Satisfactory disease-free survival * No clinical trials compared the survival outcome between IMRT and proton IMPT directly.	23,24

IMPT, intensity modulated proton therapy; IMRT, intensity modulated radiotherapy; OAR, organ at risk.

Adaptive radiotherapy and GTV shrinkage after induction chemotherapy

Recently, a new concept of radiotherapy, adaptive radiotherapy (ART), has attracted the attention of many clinicians. ART means the replanning of target design during treatment. This concept is put forward based on the fact that patients may undergo anatomical change throughout radiotherapy treatment. It has been reported that target volume shrinkage and weight loss are more commonplace in NPC patients receiving radiotherapy.²⁶

ART is effective in addressing the impact of this change on the planned dose distribution during the treatment of NPC. Chen et al noted that for NPC patients, the volume and dose distribution of OARs are common at the limit of their prescribed tolerance and replanning can be essential in ensuring these OAR doses remain within tolerance.²⁷ Further, they compared the survival outcomes in patients with or without adaptive re-planning. The 2 year locoregional relapse free survival for patients treated by ART or not were 88 and 79% respectively (p = 0.01). For patients treated by ART, all failures occurred within the high-dose planning target volume. Several studies reported a variety of time points during treatment that may be optimal for re-scanning and re-planning. Evidence indicated that anatomic changes are more pronounced in the first half of treatment, thus, ART performed in this time period is more recommended.^28–31

Identifying NPC patients who may benefit from ART is also a noticeable problem and it is difficult to reach a consensus on this issue. However, obvious variation exists in different studies identifying the ratio of patients benefiting from ART.^32–34 Brown et al carried out a prospective study involving 110 patients. In that study, only 4.5% required replanning for brachial plexus protection. Dose distributions for all structures were examined during the replanning process, and they found that the actual dose delivery was greater than planned dose. Even then, the dose increase was less than 1% in all structures except the ipsilateral parotid gland (2.8%) and contralateral parotid gland (3.6%). Meanwhile, the GTV-n coverage remained within ±105% of the prescribed dose and OAR median doses remained less than their prescribed tolerance. This phenomenon might be explained by the following reasons. In the course of RT, the volume of the tumor shrank and its relative position with adjacent anatomical structures might change accordingly. However, the coverage and dose of GTV remained unchanged, which led to the result that the planned dose in normal organs was not equal to the actual radiation dose. In addition, acute inflammatory reactions such as parotid edema might occur during radiotherapy. Volume changes of normal organs could also initiate this process.

In order to integrate a number of studies and draw a convincing conclusion, University Medical Center Groningen launched a review aiming to establish criteria to identify head and neck cancer patients benefiting from ART.³⁵ 51 studies were involved in the review. As a result, the parotid gland was the organ mostly studied with the largest volume changes during radiotherapy (26% of average volume decrease). The focus on parotid gland could be explained by the fact that radiation dose to the parotid gland was closely related to xerostomia,^36,37 which greatly compromised patients’ life qualities. Duo to the heterogeneity and potential selection criteria existing in these studies, there was no definite criteria in selecting patients for adaptive radiotherapy in NPC at present. Thus, there is a need for larger prospective studies, which include assessment of anatomic and dosimetric changes, to identify the relationships between anatomical changes and clinical outcome. The studies related to ART were summarized in Table 2.

Table 2. .

The summary of studies related to ART

Study direction	Study conclusion	Reference
Dose distribution and toxicity	I. Lower dose exposure to the normal tissues such as parotid gland under ART II. Patients received ART had better quality of life	36,38
Survival analysis	I.Lower dose exposure in OAR in ART group II. Patients in ART group achieved higher 2 year LRFS	27
Recommended time period	I.Most anatomic changes occurred in the first half of treatment II. ART was recommend performed in the first half of treatment	28–31
Identify suitable patients	* No definite criteria at present	35

ART, adaptive radiotherapy; LRFS, locoregional relapse free survival; OAR, organ at risk.

Nowadays, several scholars put forward another theory explained as follows briefly. The volume of tumor shrank after induction chemotherapy (IC). Thus, in patients with larger tumor volume, IC was recommended to reduce tumor size before radiotherapy. Further, clinician could design the target area on the basis of the renewed tumor coverage, which might reduce the radiation dose of adjacent organs. Several studies have reported the influence of induction chemotherapy on dosimetric outcomes in patients with head and neck cancers.^38,39 According to a retrospective report in locally advanced oropharyngeal cancer, average mean OAR dose was significantly lower in post-IC plans compared with pre-IC plans.³⁹ In locoregionally advanced NPC, Yu et al verified that IC regimen of paclitaxel, cisplatin and 5-fluorouracil could significantly reduce tumor volume. Moreover, the high dose region of GTV in post-IC plan was reduced with excellent short-term treatment outcome. The above results reminded us that shrinking GTV after induction chemotherapy for advanced NPC could be another choice for lowering doses exposure to the normal tissues, which potentially improved patients’ quality of life. More prospective studies with the information of long-term survival outcomes and chronic toxicities were needed to confirm this theory.

Radiotherapy and artificial intelligence

With the development of machine learning algorithms and computing power, the management of big datasets and the maturation of stable cloud platform, artificial intelligence (AI) sprang up in the last decade. The essence of AI is absorbing previous information and providing automated decision thereafter. In healthcare, AI is emerging and showing its value in radiology, pathology and ophthalmology, which are built mainly upon the interpretation of images.

The administration of radiotherapy is a complicated multitask program based on the co-operation of clinicians, physicists, dosimetrists and therapists. It is involved with multiple data transfer processes and quality controls. AI has incomparable advantages in integrating and processing data, providing optimized and efficient decisions with minimized errors and it could greatly facilitate the execution of radiotherapy. In treating nasopharyngeal carcinoma, the radiotherapy planning process is sophisticated and time-consuming given the complexity of head and neck anatomization, and it often results to planning variation in clinical practice. AI is believed to reduce subjective variations and inaccuracy of contours.

The current tendency of AI in nasopharyngeal carcinoma mainly focuses on image recognition, auto-segmentation, dose prediction. The auto-recognition and diagnosis of tumor with the use of neural networks has been achieved in skin, breast, rectal and lung cancers, etc^40–43 and outperformed many clinicians in visual tasks. A large database of medical images is usually necessary for building convolutional neural networks (CNN), then image features are extracted and targets identified through deep learning algorithms. As CNN is mostly applied to analyze visual information, images being explored vary from pathological section, radiological images and electrocardiograms. Li⁴⁴ has developed an AI-based model to detect nasopharyngeal malignancies using endoscopic pictures, and it attained an overall accuracy of 88.0%. To further achieve full utilization of the model, the combination with other parameters and radiologic images should be considered.

Automated-segmentation, especially for organ at risk (OAR), though has been developed for years, was not able to generate conformal contours especially in head and neck cancers where identifying soft tissues were of difficulties. Combining AI methodologies, from atlas-based autosegmentation to CNN, to increase the accuracy of segmentation is promising as demonstrated in several studies of head and neck cancers (HNSCC).^45–48 In NPC, males⁴⁹ have proposed a method to delineate tumor targets, and the dice similarity coefficients (DSC) reached 80.9% for GTVnx and 82.6% for clinical target volume (CTV). However, the segmentation ability differed greatly among studies and OARs. As in Ibragimov’s study,⁴⁵ the DSC for chiasm and mandible were 37.4 and 89.5% respectively. In a recently published study launched by Sun,⁵⁰ a three-dimensional CNN was applied to 818 NPC patients to develop an AI tool for automate GTV contouring, and the tool was further tested in 203 patients and compared with eight qualified radiation oncologists. The AI-generated contours showed a DSC of 0.79 in testing cohorts, improved accuracy (median DSC, 0.74–0.78, p < 0.001), reduced contouring time (by 39.4%) and intra-/interobserver variation (by 36.4 and 54.5%) in the evaluation with oncologists. Studies to test whether the tool works well with CT data or facilitates adaptive radiation recontouring are warranted.

The prior prediction of dose distribution is valued for supporting clinical decisions by improving plan quality and saving planning time. Methods to achieve it differed from atlas-based, atlas regression forest, artificial neural networks to CNN. However, practically speaking, a well-applied model is still absent for the automated plans often exceeded the dose constraints and relied upon the patterns of included data. In Tol’s⁵¹ attempt to predict dose–volume histograms for new patients in HNSCC, the model-generated plans were comparable to clinical plans only when target volume was within the range of included cases in the model. When it was applied to treat NPC,⁵² acceptable plans were only attained in 9 of 20 patients, with significant suboptimal plans existing and requiring for surveillance.

Although many AI techniques are in the developmental stage at present and unlikely to replace clinicians in the near future, the future of AI in NPC is promising. To maximize the potential of AI, it is essential to acquire authentic and reliable data from different institutions and integrate them to create effective AI algorithms.

Combining precision radiotherapy with molecular targeting

The current administration of radiotherapy in NPC generally and empirically follows the standard dose and fractionation recommended by guidelines no matter of the size, location or any other tumor parameters. However, the survival benefits brought by standard therapy has encountered bottleneck since 20–30% patients will develop local recurrence or distant metastasis afterwards. The great heterogeneity exists among individuals even with same TNM stage or under identical treatment, which suggests the potential of gene expressing profiling as a useful tool to indicate biological behavior of tumor. Thanks to the development of high-throughput technologies, the identification and intercrossing analysis of genotypic, transcriptional and epigenetic variation is much easier, which can thus be integrated into clinical practice.

There are three major parts that the identification of tumor heterogeneity may play a role in. Firstly, in-depth studies of genomic aberrations and the emergence of genetic biomarkers should shed a light on the precision screening and prediction of NPC. The precise screening of NPC among healthy individuals was conducted by Chan et al.⁵³ With the minimum detection limit of 20 EBV genomes per milliliter of plasma, a much higher proportion of early stage NPC was identified (71% vs 20%, p < 0.001). Tang⁵⁴ analyzed RNA expression and identified 137 genes in NPC tissues and 13 were incorporated in the nomogram model to predict metastasis for locally advanced NPC. Patients in high-risk group exhibited a 4.93-fold risk of metastasis (p < 0.0001).

Secondly, the incorporation of genomic information may help to dig out the biological differences and further customize the personalization of radiotherapy. Scott et al⁵⁵ developed a genome-based model to derive an optimum genomic-adjusted radiation dose, which matched with individual radiosensitivity for different cancers including HNSCC. For example, a high genomic-adjusted radiation dose suggested of high therapeutic effect for radiotherapy, which may indicate a need for deintensification of radiation dose. Before the introduction of genome-based models into clinical practice, the collection of comprehensive data from different institutes and the validation in clinical trials are required.

Thirdly, understanding the molecular alterations in the process of oncogenesis may help guide the evolution of targeted drugs. Although the whole-exome sequencing of NPC revealed a relatively low mutation rates and wide mutational diversity, patients with advanced disease exhibit a heavier mutational burden. Among them, accumulated aberration in the NF-κB, PI3K, MAPK signaling pathways were identified,^56,57 and NF-κB pathway aberrations were believed as critical to EBV-positive NPC. Phoon YP⁵⁸ found the role of tumor suppressor gene IKBB, which interplayed with the Akt/GSK3β pathway to inhibit NF-κB and thus lead to oncogenesis and angiogenesis. Other regulators of NF-κB pathway including CYLD, TRAF3, LMP-1 were also studied.^59,60 Concerning PI3K pathway, suppressor gene PTEN mutation was frequently observed, followed by PIK3CA, PIK3C2C, MTOR, etc.⁵⁶ Cai L found EBV-miR-BART1 directly targeted PTEN and induced epithelial-mesenchymal transition.⁶¹ Some fusion genes, such as UBR5-ZNF423, FGFR3-TACC3 were also detected in NPC.^62,63 However, even the future may rely on comprehensive understanding of genomic and molecular mechanisms, there’s still a long way to translate the genomic and proteomic findings to the discovery of targeted drugs.

Immunotherapy and immune checkpoint inhibitors

Over the years, a more thorough understanding over the relationship between tumorigenesis and immune dysfunctions have prompted researchers and clinicians go deep into remodeling immune functions and promoting immunotherapy. Programmed Cell Death-1 (PD-1) is mostly expressed on activated T cells and serves as an inhibitory receptor to block anti tumor T cell response upon binding to its ligand (PD-L1). Recent years, the development of PD-1 and PD-L1 inhibitors has achieved substantial improvement in preclinical studies and some clinical trials.⁶⁴ Given the abundance of tumor infiltrating lymphocytes in nasopharyngeal tumor tissues and the high expression of PD-L1 of 69% in EBV-related NPC,⁶⁵ there is a strong impetus to apply PD-1/PD-L1 antibodies to treat advanced NPC. Currently, several clinical trials exploring the role of PD-1/PD-L1 inhibitors in NPC have been conducted. Hsu C’s⁶⁶ and Ma BBY’s⁶⁷ revealed objective response rates of 25.9 and 20.5% accordingly in recurrent or metastatic NPC. In Fang et al.’s report,⁶⁸ camrelizumab (anti-PD-1 antibody) monotherapy showed an overall response of 34%. While combining with gemcitabine and cisplatin, it climbed to 91%. Other ongoing trials included a Phase II study (NCT02605967) and a Phase III trial (NCT03581786) to test the efficacy of PD-1 antibody in recurrent or metastatic NPC. Meanwhile, a Phase III trial (NCT03427827) conducted by Ma was aimed to investigate whether adjuvant PD-1 antibody could improve survival in locoregionally advanced NPC after chemoradiotherapy. The aforementioned trials are recruiting participants by far.

Before the wide application of PD-1/PD-L1 antibodies in NPC, it is of great necessity to carefully evaluate how they interact with radiotherapy to maximize combined efficacy. Radiotherapy is capable of arousing immune response by upregulating the expression of MHC-I and Fas receptors on tumor cells and enhancing the role of cytotoxic T cells.^69,70 Based on Zeng’s preclinical results of glioblastoma on mice,⁷¹ improved survival was demonstrated with radiation plus anti PD-1 therapy compared with either modality alone. Similar results were found in Deng’s study⁷² that PD-L1 was upregulated in the tumor after radiation and PD-L1 blockade enhanced the efficacy of RT through a cytotoxic T cell-dependent manner. Besides, it is gradually believed that radiotherapy to a local site is potential in generating systemic neoantigens and triggering immune surveillance in distant tumors, which was called abscopal effect.^73–75 The combination of immunotherapy and radiation may arouse the immune cells and change the tumor microenvironment by increasing secretion of inflammatory cytokines, and further evoke abscopal immune responses in metastases lesions. The abscopal effect was also observed in Deng’s study⁷² as the growth of abscopal tumors were delayed in the RT plus anti PD-L1 group. In Park’s study,⁷⁶ the combination of stereotactic radiotherapy with PD-1 blockade elicited a 66% reduction in size of nonirradiated second tumor.

However, this phenomenon may be a double-edged-sword as it also increases the expression of non-tumor-specific antigens,⁷⁷ which may give rise to systemic adverse events especially when combining with immune checkpoint inhibitors. Except for the concern about their safety profile, how to optimize the use of immune checkpoint inhibitors, in terms of deciding candidates, sequence, dose and fractionation in the conventional chemoradiotherapy settings is also under active investigation. The current mainstream view recommends the concurrent use of chemoradiation with immune checkpoint inhibitors. Dovedi et al⁷⁸ has proved that the concomitant but not sequential administration of anti-PD-L1 antibodies with radiotherapy was required to improve survival. Furthermore, RT delivered as 10 Gy in five daily fractions showed better therapeutic effect in mice. However, different studies vary in determining the optimal radiation schedule as both in Lugade’s⁷⁹ and Lee’s⁸⁰ reports, a single high-dose regimen was preferred over the conventional fractionation to trigger immune response. Hence, further studies to figure out the best way to synergize different treatment in specific circumstances are still needed.

Conclusion

There are several developing areas in treatment of NPC, which have brought obvious survival benefits to patients. During the last decades, recurrence rates of NPC have declined significantly and metastasis rates were controlled in a lower level. Different from traditional radiotherapy technology, IMRT achieved an optimal dose distribution to tumor area and minimized the dose delivery to organs at risk. Afterwards, the emergence of proton radiotherapy further decreased the dose to normal tissue and ensured the patients’ quality of life. Based on the fact that patients undergo anatomical change throughout radiotherapy treatment, the concept of ART was put forward to protect normal organ individually. How to select patients suitable for adaptive radiotherapy became the most critical issue. In future, treatment of NPC should be diversified. It is important to explore the molecular mechanism of pathogenesis and disease progression, providing the foundation to develop new drug. For example, the PD-L1 antigens expressed by NPC tumor cells have become the most popular target of immunotherapy in the personalized management era. Some advanced technologies, such as whole-genome sequencing and integration of panomics data, may also contribute to find new biomarkers and select patients for a specific therapy. Besides, with the development of computer filed, AI was created with strong ability of information integration and accurate calculation power. Thus, we have reason to believe that target design will be done accurately with the help of AI, which may replace clinicians one day.